The ability to recognize pathogens and initiate inflammatory and immunologic processes to control their spread relies on innate immune system signaling. One of the most recently identified pathogen-sensing signaling pathways involves the activation of the inflammasome, a macromolecular complex responsible for proteolytic processing of several immature cytokines (IL- 12 and IL-18 in particular). The ATP-binding protein NLRP3 acts as a central scaffold during in the assembly of the inflammasome. In addition to cytokine processing, we have recently found that signaling through NLRP3 activates a novel cell death program with morphologic and biochemical features of necrosis. The NLRP3-inflammasome can be activated by numerous stimuli known to induce IL-12 secretion, suggesting that the physiologic role of NLRP3 is to integrate the response to a range of pro-inflammatory triggers. Mutations in the nucleotide-binding domain of NLRP3 can cause inherited periodic fever syndromes. We have also recently discovered that some critical virulence factors from Staphylococcus aureus activate the NLRP3 inflammasome as well. S. aureus that express these virulence factors can cause with severe necrotizing pneumonias that are characterized by systemic inflammatory response and tissue necrosis. We believe activation of NLRP3 by mutation and pathogen-dervived virulence factors represent pathologic events that lead to dysregulated inflammation and progression diseases associated with these stimuli. We now propose to further investigate both the molecular mechanisms regulating NLRP3 activation and its role in the pathogenesis of S. aureus infections. These studies will provide crucial information in understanding inflammatory signaling processes involved in the pathogenesis of a huge array of human diseases. PUBLIC HEALTH RELEVANCE: We have found that several virulence factors from Methicillin Resistant S. aureus (MRSA) activate an innate immune signaling complex known as the inflammasome. We propose to carry out studies to understand how activation of host inflammation by the inflammasome affects the pathogenesis of MRSA infections. We also propose detailed studies into the mechanism that underlies activation of the inflammasome, which may identify targets for the development of pharmacologic agents that could improve the treatment of these deadly infections.